ACPP-AZD0156 peptide conjugate radiosensitizes tumors, boosting CD8+ T cells and survival in murine cancer models.

Tumor resistance to radiotherapy (IR) remains a significant challenge in cancer treatment, often limiting patient outcomes. While radiosensitizers can increase tumor cell kill, their clinical utility is hampered by off-target toxicity to peri-tumoral normal tissues. This necessitates strategies for spatially restricted delivery of radiosensitizers. Inhibiting ataxia-telangiectasia mutated (ATM) kinase is a promising approach, but requires tumor-specific targeting to avoid systemic side effects and harness potential immune-stimulating effects.

Researchers developed ACPP-AZD0156, an activatable cell penetrating peptide (ACPP) conjugated to the potent ATM inhibitor AZD0156. This conjugate was designed to remain cloaked until unmasked by tumor-associated matrix metalloproteinase (MMP) within the tumor microenvironment, promoting preferential tumor uptake. They evaluated its immune-stimulating and therapeutic activity with ionizing radiation (IR) in immune-competent murine cancer models. Transcriptomic profiling was used to assess immune activation, and CD8+ T-cell depletion studies established mechanistic roles. The combination with PD-1 blockade was also tested.

Combining ACPP-AZD0156 with IR significantly enhanced radiation-induced immune activation programs. Transcriptomic profiling revealed heightened type I interferon signaling and leukocyte activation network activity. Crucially, this combination stimulated robust intratumoral CD8+ T cell infiltration. > The combination of ACPP-AZD0156 and IR improved tumor control compared to non-targeted ATM inhibitor treatment. Mechanistically, the therapeutic effect of ACPP-AZD0156 + IR was abrogated by CD8+ T-cell depletion, confirming the essential role of adaptive immunity. Furthermore, the triple combination of IR, ACPP-AZD0156, and PD-1 blockade resulted in durable tumor control and long-term survival.